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NEUROPHARMACOLOGY

ST91 [2-(2,6-Diethylphenylamino)-2-imidazoline Hydrochloride]-Mediated Spinal Antinociception and Synergy with Opioids Persists in the Absence of Functional -2A- or -2C-Adrenergic Receptors

Faculty of Dentistry, McGill Centre for Research on Pain, McGill University, Montreal, Quebec, Canada (L.S.S.); Departments of Neuroscience (L.S.S., K.F.K., C.A.F., G.L.W.), Pharmacology (C.A.F., G.L.W.), and Dermatology (G.L.W.), University of Minnesota Medical School, Minneapolis, Minnesota; Department of Pharmaceutics, College of Pharmacy (K.F.K., C.A.F.), University of Minnesota, Minneapolis, Minnesota; Minnesota Center for Research on Pain, Minneapolis, Minnesota (L.S.S., K.F.K., C.A.F., G.L.W.); and Department of Anesthesiology, Wake Forest University Medical Center, Winston-Salem, North Carolina (J.C.E.)

Agonists acting at ₂-adrenergic receptors (₂ARs) produce antinociception and synergize with opioids. The ₂ARs are divided into three subtypes, _2AAR, _2BAR, and _2CAR. Most ₂AR agonists require _2AAR activation to produce antinociception and opioid synergy. The same subtype also mediates the side effect of sedation, which limits the clinical utility of these compounds. Identification of a non-_2AAR-mediated antinociceptive agent would enhance the therapeutic utility of ₂AR agonists in pain management. Previous studies have suggested that the ₂AR agonist ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride] has a nonsedating, non-_2AAR mechanism of action. We examined the pharmacology of spinal ST91 and its interaction with the -opioid agonist deltorphin II (Tyr-D-Ala-Phe-Glu-Val-Val-Gly amide) in mice lacking either functional _2AARs or _2CARs. All drugs were administered by direct lumbar puncture, and drug interactions were evaluated using isobolographic analysis. In contrast to the majority of ₂AR agonists, ST91 potency was only moderately reduced (3-fold) in the absence of the _2AAR. Studies with the ₂AR subtype-preferring antagonists BRL-44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole maleate) and prazosin [[4-(4-amino-6,7-dimethoxy-quinazolin-2-yl) piperazin-1-yl]-(2-furyl)methanone] and the pan-₂AR antagonist SKF-86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1-H-3-benzazepine) suggest a shift from _2AAR to the other ₂AR subtype(s) in the absence of _2AAR. Antinociceptive synergy with deltorphin II was preserved in the absence of either _2AAR or _2CAR. In conclusion, ST91 activates both _2AAR and non-_2AAR subtypes to produce spinal antinociception and opioid synergy. This study confirms that the spinal pharmacology of ST91 differs from that of other ₂AR agonists and extends those data to include spinal synergy with opioid agonists. The unique profile of ST91 may be advantageous in pain management.

Address correspondence to: Laura S. Stone, Faculty of Dentistry, McGill Centre for Research on Pain, 3640 University Street, Montreal, Quebec H3A 2B2, Canada. E-mail: laura.s.stone{at}mcgill.ca